title: Target-selective drug delivery through liposomes labeled with oligobranched neurotensin peptides.
abstract: The structure and the in vitro behavior of liposomes filled with the cytotoxic drug doxorubicin (Doxo) and functionalized on the external surface with a branched moiety containing four copies of the 8-13 neurotensin (NT) peptide is reported. The new functionalized liposomes, DOPC-NT₄Lys(C₁₈)₂, are obtained by co-aggregation of the DOPC phospholipid with a new synthetic amphiphilic molecule, NT₄ Lys(C₁₈)₂, which contains a lysine scaffold derivatized with a lipophilic moiety and a tetrabranched hydrophilic peptide, NT8-13, a neurotensin peptide fragment well known for its ability to mimic the neurotensin peptide in receptor binding ability. Dynamic light scattering measurements indicate a value for the hydrodynamic radius (RH) of 88.3±4.4 nm. The selective internalization and cytotoxicity of DOPC-NT₄ Lys(C₁₈)₂ liposomes containing Doxo, as compared to pure DOPC liposomes, were tested in HT29 human colon adenocarcinoma and TE671 human rhabdomyosarcoma cells, both of which express neurotensin receptors. Peptide-functionalized liposomes show a clear advantage in comparison to pure DOPC liposomes with regard to drug internalization in both HT29 and TE671 tumor cells: FACS analysis indicates an increase in fluorescence signal of the NT₄-liposomes, compared to the DOPC pure analogues, in both cell lines; cytotoxicity of DOPC-NT₄ Lys(C₁₈)₂-Doxo liposomes is increased four-fold with respect to DOPC-Doxo liposomes in both HT29 and TE671 cell lines. These effects could to be ascribed to the higher rate of internalization for DOPC-NT₄ Lys(C₁₈)₂-Doxo liposomes, due to stronger binding driven by a lower dissociation constant of the NT₄-liposomes that bind the membrane onto a specific protein, in contrast to DOPC liposomes, which approach the plasma membrane unselectively.
authors.affiliation: Laboratory of Molecular Biotechnology, Department of Molecular Biology, University of Siena, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Falciani
authors.forename: Antonella
authors.initials: A
authors.lastname: Accardo
authors.forename: Jlenia
authors.initials: J
authors.lastname: Brunetti
authors.forename: Diego
authors.initials: D
authors.lastname: Tesauro
authors.forename: Barbara
authors.initials: B
authors.lastname: Lelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.forename: Luisa
authors.initials: L
authors.lastname: Bracci
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Morelli
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D016503:Drug Delivery Systems; D006801:Humans; D057446:Hydrodynamics; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D009496:Neurotensin / Q000737:chemistry / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics; D012208:Rhabdomyosarcoma / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D010446:Peptide Fragments; D015060:1,2-Dipalmitoylphosphatidylcholine; D009496:Neurotensin; C054381:neurotensin (8-13); D008239:Lysine